Current antiobesity drugs have limited efficacy and numerous side effects. Crowley, V. E., Yeo, G. S. & O'Rahilly, S., Nat. Rev. Drug Discov 1, 276-86 (2002). With obesity reaching epidemic proportions worldwide, there is a pressing need for the development of adequate therapeutics in this area. In recent years, hormones and neuropeptides involved in the regulation of appetite, body energy expenditure, and fat mass accumulation have emerged as potential antiobesity drugs. McMinn, J. E., Baskin, D. G. & Schwartz, M. W., Obes Rev 1:37-46 (2000), Drazen, D. L. & Woods, S. C., Curr Opin Clin Nutr Metab Care 6:621-629 (2003). At present, however, these peptides require parenteral administration. The prospect of daily injections to control obesity is not very encouraging and may limit the use of these drugs.
One such peptide, PYY, is secreted postprandially by endocrine cells of the distal gastrointestinal tract and acts at the hypothalamus signaling satiety. Batterham, R. L. et al., Nature 418:650-654 (2002). Recent studies have shown that fasting and postprandial PYY levels are low in obese subjects, which may account for their high appetite and food consumption. When administered intravenously, it suppresses appetite and food intake in both lean and obese subjects. Batterham, R. L. et al., N Engl J Med 349:941-948 (2003). Other peptides from the pancreatic peptide (PP) family, like peptide YY fragments (e.g. PYY[3-36]), and PYY agonists (including those not in the PP family) also suppress appetite. Its oral activity, however, is negligible due to its low absorption and rapid degradation in the gastrointestinal tract.
PYY Cancer, Cachexia and Malnutrition: PYY is also secreted by various cancer cells: lung, ovarian, prostate, breast and Barrett's adenocarcinoma, and could act as a marker for or a target for treatment of these other malignancies. Treatment modalities could be directed toward the effects of PYY on cellular apoptosis and/or vascular endothelial growth factor.
PYY has been identified in several carcinoid tumors, and a decreased expression of PYY may be relevant to the development and progression of colon adenocarcinoma. Treatment with PYY decreases growth in pancreatic and breast tumors, most likely through a reduction in intracellular cAMP. Furthermore, PYY has antiproliferative and proapoptotic effects in Barrett's cancer cells. Combined PYY and vitamin E have significant additive antiproliferative effects on breast cancer cell lines regardless of their hormone receptor status. In addition, PYY and vitamin E have growth inhibitory effects on hormone-refractory prostate and pancreatic cancer cells. A biologically active form of vitamin E, alpha-tocopherol succinate (ATS), has been shown to induce apoptosis of hormone-refractory prostate cancer in vitro and inhibit cell growth in vivo.
Taken together, the evidence suggests a potential role for PYY as a therapeutic agent for the treatment or attenuation of multiple cancers.
In cancer patients, PYY may also improve malnutrition that results from iatrogenic causes or cachexia associated with advanced disease. PYY plays a significant role in multiple aspects of cancer from regulation of cell growth to potential therapeutic applications.
PYY and Acute Pancreatitis: Acute pancreatitis (AP) is a disease characterized by inflammation. PYY inhibits NF-k translocation to acinar nuclei in TNF-a-induced AP. Targeted inhibition of transcription factors with PYY may have therapeutic potential in attenuating the progression of pancreatitis.
PYY and Other Gastrointestinal Uses: Because of its slowing effects on gastric motility, PYY has additional potential uses, for example in spastic/irritable bowel, diabetes gastroenteropathy, inflammatory bowel diseases, celiac disease, systemic sclerosis and post-intestinal resection state.
Jean Reubi, Mathias Gugger, Beatrice Waser Eur J Nucl Med Mol Imaging. 2002 July; 29(7):855-62. Epub 2002 Apr. 20. Co-expressed peptide receptors in breast cancer as a molecular basis for in vivo multireceptor tumour targeting. Grise K R, Rongione A J, Laird E C, McFadden D W. Peptide YY inhibits growth of human breast cancer in vitro and in vivo. J Surg Res. 1999 April; 82(2):151-5. Matsuda K, Maehama T, Kanazawa K. Strumal carcinoid tumor of the ovary: a case exhibiting severe constipation associated with PYY. Gynecol Oncol. 2002 October; 87(1):143-5. Yamashita Y, Miyahara E, Shimizu K, Toge T, Adrian T E. Screening of gastrointestinal hormone release in patients with lung cancer. In Vivo. 2003 March-April; 17(2):193-5. Yu A, Somasundar P, Balsubramaniam A, Rose A T, Vona-Davis L, McFadden D W. J Surg Res. 2002 Jun. 1; 105(1):65-8. Vitamin E and the Y4 agonist BA-129 decrease prostate cancer growth and production of vascular endothelial growth factor.
At least five distinct neuropeptide Y (NPY) receptors are known to exist, and studies suggest that at least one additional subtype of NPY receptor may exist in rat brains. Dumont, Y., Moyse, E., Fournier, A., Quirion, R., J. Pharmacol Exp. Ther., Jun. 9, 2005; Evidence for the Existence of an Additional Class of Neuropeptide Y Receptor Sites in the Rat Brain.
In the delivery to animals of PYY and PYY agonist, barriers are imposed by the body. Examples of physical barriers are the skin, lipid bi-layers and various organ membranes that are relatively impermeable to certain active agents but must be traversed before reaching a target, such as the circulatory system. Chemical barriers include, but are not limited to, pH variations in the gastrointestinal (GI) tract and degrading enzymes.
These barriers are of particular significance in the design of oral delivery systems. Oral delivery of PYY and PYY agonist would be the route of choice for administration to animals if not for such biological, chemical, and physical barriers. These agents may be rapidly rendered ineffective or destroyed in the gastro-intestinal tract by acid hydrolysis, enzymes, and the like. In addition, the size and structure of macromolecular drugs may prohibit absorption. As a result, the oral administration of protein and peptide drugs is challenging due, in part, to their low absorption and rapid degradation.
Earlier methods for orally administering vulnerable pharmacological agents have relied on the co-administration of adjuvants (e.g., resorcinols and non-ionic surfactants such as polyoxyethylene oleyl ether and n-hexadecylpolyethylene ether) to increase artificially the permeability of the intestinal walls, as well as the co-administration of enzymatic inhibitors to inhibit enzymatic degradation. Liposomes have also been described as drug delivery systems for insulin and heparin. However, broad spectrum use of such drug delivery systems is precluded in part because: (1) the systems require toxic amounts of adjuvants or inhibitors; (2) suitable low molecular weight cargos, i.e., active agents, are not available; (3) the systems exhibit poor stability and inadequate shelf life; (4) the systems are difficult to manufacture; (5) the systems fail to protect the active agent (cargo); (6) the systems adversely alter the active agent; or (7) the systems fail to allow or promote absorption of the active agent.
More recently, proteinoid microspheres have been used to deliver pharmaceuticals. See, for example, U.S. Pat. Nos. 5,401,516; 5,443,841; and Re. 35,862. In addition, certain modified amino acids have been used to deliver pharmaceuticals. See, for example, U.S. Pat. Nos. 5,629,020; 5,643,957; 5,766,633; 5,776,888; and 5,866,536.
According to Batterham et al., Nature 418:650-654 (2002), which is hereby incorporated by reference, the peptide YY [3-36] system may provide a therapeutic target for the treatment of obesity.
International Publication No. WO 02/47712 and U.S. Patent Publication No. 2002/0141985 disclose methods for treating obesity and diabetes with peptide YY and peptide YY agonists, such as peptide YY[3-36].
International Publication No. WO 2004/104018 discloses a composition comprising at least one delivery agent compound and at least one of peptide YY (PYY) and a PYY agonist.
There is still a need for simple, inexpensive delivery systems for delivering peptide YY and PYY agonists which are non-invasive and which are convenient, so as to increase patient compliance and acceptability.